Pharmacogenetics and pgx

Pharmacogenetics

The study of the influence of genetic factors on the response to, and toxicity of foreign chemicals.

Pharmacogenomics

The relation of the individual's genetic makeup to their response to specific drugs.

Pharmacokinetics (PK)

What the body does to the drug. This includes absorption, distribution, metabolism, and excretion.

Pharmacodynamics (PD)

What the drug does to the body. This involves the drug's interaction with its target and the resulting effects.

Genetics

The study of inheritance. This can be at the population, Mendelian, or molecular level.

Human Genome

Human DNA is organized in 23 pairs of chromosomes, with one member of each pair from each parent (haploid). Humans are diploid, having two copies of almost every nucleotide of DNA.

Pharmacogenetic Variants

Variations in an individual's genes that can affect their response to drugs. These can be classified pharmacologically (pharmacokinetic or pharmacodynamic) or genetically (monogenic or polygenic).

Polymorphism

The occurrence of different forms or types of individuals among the members of a species. In pharmacogenetics, this often refers to genetic variations that lead to differences in drug metabolism or response, such as in CYP2D6.

Extensive Metabolizers (EM)

Individuals with a typical ability to metabolize certain drugs, often associated with having a normal number of functional gene copies for drug-metabolizing enzymes like CYP2D6.

Poor Metabolizers (PM)

Individuals with reduced or absent ability to metabolize certain drugs, often due to non-functional or deleted gene copies for drug-metabolizing enzymes like CYP2D6.

Ultra-rapid Metabolizers (UM)

Individuals with increased ability to metabolize certain drugs, often due to multiple functional gene copies for drug-metabolizing enzymes like CYP2D6. This can lead to lower than expected drug concentrations or increased formation of active metabolites.

CYP2D6

A cytochrome P450 enzyme that exhibits significant genetic polymorphism, affecting the metabolism and thus the response to many drugs like codeine, dextromethorphan, tamoxifen.

CYP2C9

Another cytochrome P450 enzyme with genetic polymorphisms that affect the metabolism of drugs like S-warfarin.

CYP2C19

A cytochrome P450 enzyme that is also subject to genetic polymorphisms affecting drug metabolism.

TPMT

Thiopurine S-methyltransferase, an enzyme involved in the metabolism of thiopurine drugs used in leukemia therapy 6MP, which exhibits genetic polymorphism affecting drug safety.

Pharmacodynamic Variants

Genetic variations that affect how the drug acts on the body, such as variations in drug target receptors. An example is variation in the beta2-adrenergic receptor affecting response to isoproterenol and salbutamol.

Personalized Medicine

The use of an individual's genetic and other information to tailor their medical care, aiming to provide the right dose of the right drug in the right patient at the right time. This is often enabled by genetic technologies.

Therapeutic Index

A measure of drug safety, often defined as the ratio of the toxic dose (TD50) to the effective dose (ED50). Drugs with a narrow therapeutic index are often candidates for pharmacogenetic testing because small changes in plasma levels can significantly alter effectiveness or toxicity.

INR (International Normalized Ratio)

A standardized measure of blood clotting used to monitor the effectiveness of anticoagulant therapy with warfarin. Genetic variations in enzymes like CYP2C9 can significantly affect warfarin sensitivity and INR.

DPD (Dihydropyrimidine Dehydrogenase)

An enzyme involved in the metabolism of the chemotherapy drug 5-fluorouracil (5FU). Deficiency in DPD due to genetic variants can lead to severe toxicity.

PGx Testing

Pharmacogenetic testing, which involves analyzing an individual's genes to predict their response to specific medications.

Reaction Phenotyping

Determining which specific enzymes, such as P450 isoforms, are responsible for metabolizing a particular drug. This can be done using in vitro tests with human tissues or cloned enzymes.

Single Nucleotide Polymorphisms (SNPs)

nucleotide substitutions that occur frequently in populations. they are the most abundant tyoe of genetic variant and can be useful mapping markers for finding disease genes. SNPs influence how we respond to medications

Genetic Classification of pharmacogenetic variants

polymorphic, rare or polygenic

discovery of CYP2D6 polymorphism

first discovered in the 1970s by clinicans who saw variable effectiveness and toxicity of debrisoquine and spartein

Dextromethophan (DM)

a safe in vivo probe for CYP2D6 function

Tamoxifen

breast cancer treatment intially metabolized by CYP3A4 into an intermediate, which is then metabolized by CYP2D6 to its main active metabolite. extensive metabolizer have highest survival trait

omeprazole

proton pump inhibitor, varaible CYP2C19. Poor metabolizers have a better reduction of stomach acidity

Warfarin increased risk for bleeding

increased risk for bleeding is not solely related to genetic variation in CYP2C9 VKORC1- Vit K epoxide reductase CYP2F4- Vit k oxidase Factor V